Prediction Of Reactive Side

PREDICTION OF REACTIVE SIDE OF MOLECULE FOR EPOXIDATION, CATALYTIC REDUCTION AND 1,3 DIPOLAR ADDITION BY LOCAL REACTIVITY DESCRIPTOR. R.Margabandu, K.Subramani*. Department of Chemistry, Islamiah College, Vaniyambadi, PIN- 635751, Tamil Nadu , India. Email: [email protected]

Abstract If any molecule has more than one reactive side for specific reagent in that case the preferred reactive side is theoretically determined by means of local reactivity descriptor called local softness for electrophilic, nucleophilic and free radical attack. In the computational chemistry selection of method and basis set are important, wheather semiempirical (or) ab initio (or) DFT ,for calculation.The above selections are very important because this decides the time of calculation. In this work we used semi-empirical ZINDO Hamiltonian for calculation of local softness. This method is very faster than others and this hamiltonia yields result which is in agreement with practical. Key Words : Quantum mechanical, Local Softness, Reactive side INTRODUCTION To day challenge for the chemist is to prepare the compound having desired activity for the different field like drug discovery, polymer industry, corrosion inhibition and so on. if our molecule has more than reactive side, when we write scheme for desired compound, for specific reagent then first preferred reactive side is determined by computational method. In Computational method first geometry of molecule to be optimized by molecular mechanics or quantum mechanical method after that value of quantum mechanical descriptor like Energy of HOMO, Energy LUMO,Diploe moments,Charge density on atoms, Bond order between the two bond, Ionisation potential and electron affinity are calculated. The desired information for molecule can be derived from the value of quantum mechanical descriptor.The type descriptor value required is depends upon type of information to be derived. The Computational method has changed the trend and this can be simply written like as follows. Optimization of structure → quantum mechanical descriptor calculation → prediction of reactivity By the above method we can save the time, money and hazardous generation by avoiding trial and error method for synthetic scheme. If predicted reactive side is not desirable then we go for different substitution (electron withdrawing and donating) to get desirable reactive side.

RESULT AND DISCUSSION Global reactivity descriptors The several global reactivity descriptors of molecules such as Hardness (η),chemicalpotential(µ), Softness(S) and electronegativity (χ)[3,4] are defined as. η = ½ (I − A)

(1)

µ = −½ (I + A)

(2)

χ=-µ S = 1/ η

(3) (4)

I = Ionization energy , A= Electron affinity I= E + - E A= E - E¯ The condensed Fukui functions are local reactivity descriptor. In practice a more convenient way of calculating the condensed Fukui functions[5] f(r) for an atom k in a molecule are expressed as: fk+ = [q k (N+1) − q k (N)] for nucleophilic attack

(5)

fk– = [q k (N) − q k (N-1)] for electrophilic attack

(6)

fko = ½[q k (N+1) − q k (N-1)] for radical attack

(7)

where q is the electronic population of atom k in the molecule under consideration.N,N1 and N+1 are the electron density of neutral molecule, cation and anion respectively on atom k of the molecule k

The local softness (sª )s to an atom site say k, can be written as, k

s ªk = f ª k S

(8)

ª =+/ ° / – where a = +/– / ° refer to nucleophilic, electrophilic and radical attacks, respectively

In most of the case local softness has the values of positive and negative[6] so this mixed sign value of local softness leads to confusion to decide preferred side of attack hence local softness can be written as follows Three different types of condensed atomic descriptors (sf )ªk can be [6]readily obtained as, i.e. (sf) ¯k = ( f ¯k)2 S

(9)

governing electrophilic attack, (sf) +k = ( f +k)2 S

(10)

governing nucleophilic attack, (sf) °k = ( f ° k)2 S

(11)

governing radical attack, The region of molecule having maximum value of local softness has the preference for electrophilic,nucleophilic and free radical attack. The most useful and important application of local softness is interpretation and prediction of reaction mechanism, and regio-selectivity. 1.Reactive side for epoxidation Epoxidation of olefinic double bond can be achieved by two reagent they are 1) hydrogen peroxide in sodium hydroxide.2) m-chloroperoxybenzoic acid. Only olefinic double bond having conjugation with carbonyl double can be converted to epoxide by hydrogen peroxide in sodium hydroxide. Double bond does not have conjugation with another double bond can be converted to epoxide by m-chloroperoxybenzoic acid. Mechanism for epoxidation by hydrogen peroxide and m-chloroperoxybenzoic acid are as follow. From the mechanism it is clear that epoxidation by m-chloroperoxybenzoic acid proceeds through nucleophilic attack and epoxidation by hydrogen peroxide in sodium hydroxide proceeds through electripkilic attack. 1. General Mechanism. COOH H

O

O

O

+

O

Cl

2.

Cl

_

O

O

O

O H

H2O2,NaOH

O

_ OOH

O

O

Example 1

O

O

O 1

3

C

6

C

C

O

5

C

H2O2,NaOH

O

O

A

Epoxydation at 1,3 double bond

O

3 1

O

C 6

Epoxydation at 5,6 double bond

C 5

C

C

O

H2O2,NaOH

1

O

3

C

6

C

C

5

C

O B

1 Epoxidation by hydrogen peroxide in sodium hydroxide is proceeding through nucleophilic attack so we can conclude that the region of molecule having higher value of local softness for nucleophilic attack is the preferred region for epoxidation by the hydrogen peroxide in sodium hydroxide. The 25(R)-1,4,6-spirostatrien-3-one (1) has two reactive side for epoxidation by hydrogen peroxide in sodium hydroxide so possible isomer are A and B.In practical we got the isomer A[7]. Our theoretical calculation also predicts same isomer by the local softness calculation. Theoretical results are as follows. The quantum mechanical descriptor are shown in the table 1 and local softness for nucleophilic attack are shown in the table 2. It is clear that C3 has higher value for local softness of nucleophilic attack and the possible isomer is(A) in agreement with practical one.

Table : 1

Table 2

Descriptor

Value(au)

Energy of HOMO

-0.3158

Energy of LUMO

-0.0235

Energy of E,Neurtral

-216.257

Energy of E+, Cation

-216.001

Energy of E-,Anion

-216.313

Ionization Potential

0.2556

Electron affinity

Atom No 1 3 5 6

0.056

Hardness

0.0998

Softnes

10.02004

(sf)+ 0.006 0.077 0.057 0.008

Example 2 O O

OH O

6

5

C

C

8 7

C

O

C

A

m-CPBA O Epoxydation at 6,7 double bond

O O Epoxydation at 7,8 double bond m-CPBA HO

6

5

C

C

8 7

C

C

25(R)-4,6-spirostadiene-3?-ol

OH

5

6

C

C

8 7

C

C

O B

2 Epoxidation by m-Chloroperoxybenzoic acid is proceeding through electrophilic attack so we can conclude that the region of molecule having higher value of local softness for

electrophilic attack is the preferred region for epoxidation by the mChloroperoxybenzoic acid. The 25(R)-4,6-spirostadiene-3β-ol[7] (2) has two reactive side for epoxidation by m-chloroperoxybenzoic acid so possible isomer are A and B. In practical we got the isomer a and our theoretical calculation also predicts same isomer by the local softness calculation. Table 3 & 4 shows the quantum mechanical descriptor and local softness for electrophilic attack of the 25(R)-4,6-spirostadiene-3β-ol(2) respectively. The local softness is higher for the C6 hence possible product is A. Table : 3 Descriptor Energy Atom of HOMO (sf)No Energy of LUMO 0.116 Energy5of E,Neurtral Energy6of E+,0.144 Cation 7 0.037 Energy of E-,Anion 8 Potential 0.128 Ionization Electron affinity Hardness Softnes

Value(au) -0.2964 0.0283 -219.91 -219.638 -219.918 0.2722 0.0083 0.13195 7.57863

Table ; 4

Example 3 R1

N O O O

Et2O,RT, 16hr

O

A

1 O

2

C

_

C

+

O

+ N

O

O

Nu_ attack on C1 R1 Nu_ attack on C2 R1

N O

Et2O,RT, 16hr O O

B

3 1, R1=C6H5 2, R1=4-ClC6H4 3, R1=4-MeOC6H5 4,R1=CH=CHC6H5 5,R1=CH(CH3)2

O

The 5-Methoxy-2(5H)- Furanone (3) undergoes[8] 1,3 dipolar addition and there is possibility of getting two isomer A & B since 5-Methoxy-2(5H)- Furanone is not a symmetrical one. In practical we got only Isomer A with five different (R1) and our theoretical result also predicts the same. Table 5 & 6 shows the quantum mechanical descriptor value and local softness for nucleophilic attack respectively.From the table 6 it is clear that C1 of the molecule (3) is the preferred side for attack of nucleophilic portion of 1,3 dipolar hence theoretical prediction in agreement with practical. Table : 5

Table : 6

Descriptor Energy of HOMO Energy of LUMO Energy of E,Neurtral Energy of E+, Cation Energy of E-,Anion Ionization Potential Electron affinity Hardness Softnes Atom No (sf)+ 1 0.193 2 0.151

Value(au) -0.3822 -0.0215 -68.7579 -68.4198 -68.7963 0.3381 0.0384 0.14985 6.67334

Example 4 H N

Ph

O O 9 N

5

O O

4 O

O

Pd/C Ph

O

A

Reduction of 9,5 bond Pd/C

O 1 rReduction of 4,1 bond

N

Ph

O O O

OH

B

4 The nitrile oxide adduct[8] of 5-Methoxy-2(5H)- Furanone (Molcuele 4) undergoes the catalytic reduction and there is possibility of getting two isomer A & B since it contains two susceptible double bond. In practical we got the isomer A. Table7 & 8 Shows the quantum mechanical descriptor value and local softness for radical attack respectively.The local softness for C5 is higher than C4 even if we consider hetero atom N9 is higher than O1 so possible isomer is A. This is in agreement with practical result.

Table 7

Descriptor

Value(au)

Energy of HOMO

-0.3245

Energy of LUMO

-0.0283

Energy of E,Neurtral

-132.543

Energy of E+, Cation

-132.244

Energy of E-,Anion

-132.599

Ionization Potential

0.2998

Electron affinity

0.0561

Hardness Softnes

Table8 Atom No

(sf)0 4

0.00106

5

0.1306

1

0.00125

9

0.285

0.12185 8.206812

EXPERIMENTAL SECTION All the molecule were initially geometry optimized in molecular mechanics using UFF force field with convergence limit of 10 x 10-1 kcal/mol/Ang then the coordinate generated in UFF has been taken for geometry optimization(neutral molecule) at AM1( semi-empirical) in RHF method with convergence limit of 10 x 10-10 kcal/mol. The optimized geometry at AM1[11] level has been taken for single point energy calculation in ZINDO method at neutral,cation and anion[18]. The result of ZINDO method is used for local softness calculation[9,10].The geometry optimization were carried out in Arguslab software[12-17]. The geometry optimized molecule are shown below.

1

2

3

4 CONCLUTIONS The ZINDO( semi-empirical) method is sufficient to calculate reactive side of molecule for electrophilic, nucleophilic and radical attack for small and big molecule by means of local softness. The ZINDO Hamiltonian calculates faster than other Hamiltonian hence It is not necessary to choose other time consuming Hamiltonian or ab initio or DFT for reactive side prediction. REFFERENCES 1. Abhijit Chatterjee. J. Chem. Sci. Vol;117, No.5, septemper 2005, pp533-539.

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